Amino-acylamino-acylamino-penicillanic acids



3,268,516 AMHNU-ACYLAMllN-ACYLAMINO- PENIULLANIC AClDS Norman H. Grant, Wynnewood, and Harvey E. Album,

West Chester, Pa, assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 7, 1964, Ser. No. 358,082 8 Claims. (Cl. 260239.1)

Where R is of the group consisting of hydroxy and alkyl; 11:2 to 7; and

Y is of the group consisting of:

(1) IU-(ylI-I-O 0- where R is of the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkaryl, and substituted alkaryl; and

R is of the group consisting of alkyl and aryl;

Where 11:2 to 9;

1'1 1 INR where R R R and R are of the group consisting of hydrogen, alkyl, nitro, sulfo, amino, halo and hydroxy; R and R R and R and R and R when respectively joined complete a ring of the group consisting of aryl and alicyclic; and R is of the group consisting of hydrogen and lower alkyl;

Where R R R and R are of the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halo, amino and nitro;

R-S(CH2)n(IJHC O United States PatentO in which case A is a second residue of the penicillanic acid derivative of Formula I above, and n=1 to 5;

Hill

where R is of the group consisting of hydroxy and alkyl, and 11:2 to 7; and

(7) I-I2NC O-(CHz)n-CHC 0- where n=1 to 4.

The new compounds of the series defined above show desirable broad spectrum antibacterial activity and are useful as therapeutic agents in poultry and mammals, including man, in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria, upon either parenteral or oral administration. They also have use as nutritional supplements in animal feed.

The general process for preparing the aforesaid novel amino-acylamino-acylamino-penicillanic acids is described and claimed in said copending application and comprises generally the reaction of a 4-substituted-2,5-oxazolidine dione (also known as an N-carboxy-amino acid anhydride) with a 6-(amino-acylamino)penicillanic acid under controlled conditions. Methods for the preparation of the N-carboXy-arnino acid anhydride and 6-(aminoacylamino)penicillanic acid reactants suitable for use in the process are also described in or referred to in said copending application.

In a preferred method for preparing the amino-acylamino-acylamino-penicillanic acids of the present invention, the 4-substituted-2,5-oxazolidinedione chosen is reacted with the selected 6-(a-aminmacylamino)penicillanic acid in approximately equimolar quantities in a cold aqueous solution in a pH range from about 3.8 to about 7- 4 and preferably in the range 4.77'.0. The mixture is stirred for several hours at a temperature from just above the freezing point of the aqueous mixture to about 37 C., and preferably in the range 0-10 C. Although not essential, it may be preferred to include a buffer having an ionic strength of about 0.02, preferably about 0.3, to aid in keeping the reaction mixture within the required pH range. Suitable buffers for maintaining the desired pH may be any mixture of organic or inorganic water-soluble acids, bases, or salts such as sodium acetateacetic acid, calcium acetate-acetic acid, pyridine acetic acid, formic acid-ammonia, etc. Alternatively, the reaction mixture may be maintained Within the requisite pH range by careful addition of a base such as NaOH or the like.

The following examples are illustrative of the invention, but are not to be considered necessarily limitative thereof.

EXAMPLE I 6-[L-I-(Z-aminoacetamido)-2-pyrr0lidinecarboxamido] penicillanic acid Mix 312 mg. (1 millimole) of 6-(L-2-pyrrolidinecarboxamido)penicillanic acid with mg. (1 millimole) of the N-carboxyanhydride of glycine in 25 ml. of icecold water. Stir at 12 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freeze-dry the filtrate. The product is active against both Staph. aureus and E. coli.

3 EXAMPLE 11 When in the procedure of Example I, the N-carbxyanhydride of glycine is replaced by 1 millimole of the N-carboxyanhydride of (1) Daphenylglycine (2) D-leucine (3) 1-aminocyclobutanecarboxylic acid (4) l-aminocyclopentanecarboxylic acid (5) l-aminocyclohexanecarboxylic acid (6) authranilic acid (7) 2-amino-5-nitrobenzoic acid (8) Z-rnethylamino-S-nitrobenzoic acid (9) 'D-tryptophan respectively, the following corresponding penicillin derivatives, all active against Gram-positive and Gramnegative microorganisms, are produced:

(1) 6- [L-1-(D-Z-amino-2-phenylacetamido)-2-pyrrolidinecarboxamido]pencillanic acid (2) 6-[L-l-(D-2-amino-4-methylvaleramido)-2-pyrrolidiuecarboxamido]pencillanic acid (3) 6-[L-1-(1-aminocyclobutanecarboxamido)-2-pyrrolidinecarboxamido]pencillanic acid (4) 6-[L-1-(1-aminocyclopentanecarboxarnido)-2-pyrrolidinecarboxamido]penicillanic acid (5) 6- [L-1-( 1-aminocyclohexanecarboxamido) -2-pyrrolidinecarboxamido]pencillanic acid (6) 6-[L-I-(Z-aminobenzamido)-2-pyrrolidinecarboxamido]penicillanic acid (7) 6-[L-1-(Z-amino-S-nitrobenzamido)-2-pyrrolidinecarboxamido1penicillanic acid (8) 6-[L-1-(Z-methylamino-S-nitrobenzamido) -2-pyrrolidinecarboxamido]penicillanic acid (9) 6- [L-1-(D-a-aminoindole-3-propionamido) -2-pyrrolindinecarbox-amido]penicillanic acid.

EXAMPLE III When in the procedure of Example I, the N-car-boxyanhydride of glycine is replaced by 1 millimole of the N-carboxyanhydride of 1) 1-aminocyclopropanecarboxylic acid (2) 1-amin0cyclodecanecarboxylic acid (3) 2-amino-3-naphthoic acid (4) 2-methylamino-5-nitrobenzoic acid (5) L-a-amino-5-methylindole-3-propionic acid (6) L-a-amino-5-ethylindole-3-propionic acid (7) L-a-amino-5-meth0xyindole-3-propionic acid (8) D-2-amino-3-(ethy1thio)-propionic acid (9) DL-2-amino-3-(-methylthio)-propionic acid ('10) DL-2-amino-7-(methylthio)-heptanoic acid (11) D-ethionine (12) DL-I2-ethylarnino-2-phenylglycine 13) DL-Z-amylamino-Z-phenylglycine (14) 2-carboxytrimethyleneimine 15) 2-carboxyoctamethyleneimin (16) D-phenylalanine' (1,7) Dbphenylsarcosine (18) Naphenylglycine (19) 6-pro1ine (20) DL-o-ethoxyphenylglycine (21) L-cystinei (22) Z-amino-S-ehlorobe'nzoic acid (23) 2-amino-5-methylbenzoic acid the corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced.

EXAMPLE IV Whenin the procedure of Example I, the 6-(L-2-pyrrolidine carboxamido)penicillanic acid is replaced by 1 millimole of 6-(DL-octahydro-lH-azonine-Z-carboxamido)penici-llanic acid, the corresponding penicillin product, active against both Gram-positive and Gram-negative microorganisms, is produced.

I-NY

where R is of the group consisting of hydroxy and alkyl;

n=2 to 7; and

Y is of the group consisting of:

(1) R GHCO wherein R is of the group consisting of hydrogen, lower alkyl, phenyl, (lower)alkylphenyl, (lower) alkoxyphenyl, aminophenyl, nitrophenyl, chloropheny-l, indolo (lower)alkyl, (lower) a lkylindolo(lower)alkyl, and (lower) alkoxyindoloflower)alkyl; and R is of the group consisting of hydrogen, lower alkyl,

and phenyl;

((3112):: CCO

where n=2 to 9;

R Hl IR wherein R R R and R are of the group consisting of hydrogen, alkyl, su-lfo, nitro and chloro; R and R when joined complete a naphthylene ring;

and R is of the group consisting of hydrogen and lower alkyl;

twhere R R R and R are of the group consisting of hydrogen, lower alkyl and lower alkoxy;

:where Whe re R is of =the group consisting of hydroxy and alkyl, and n=2 to 7; and

where n=1 to 2.

2. 6-[L-1-(2 aminoacetamido) 2-pyrro1idinecarboxamido1penici1lanic acid.

3. 6-[L-1-(D-2 amino-4-methylva1eryl) 2-pyrr01idinecarboxamido] pencillanic acid.

4. 6-(L-1-[D-amin0(phenyl)acetyl] 2-pyrr01idinecarboxarnido)penici1lanic acid.

5. 6-[L-1 (1-aminocyc10butanecarbonyi) 2-pyrro1idinecarboxamido]penicillanic acid.

6. 6-[L-1-(2 aminobenzoyD-Z pyrrolidinecarboxamido1penici-1lanic acid.

7. 6-[L-1-(2 amino-S-nitrobenzoyD-Z pyrrolidinecarboxamido1penici11anic acid.

8. 6-[L-1-(D-a-aminoindo1e-3 propionyD-Z pyrrolidinecarboxamido] penicillanic acid.

No references cited.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

JAMES W. ADAMS, 111., Assistant Examiner. 

1. A COMPOUND OF THE FORMULA: 